Process Validation Guidance—Redux

When the FDA issued its draft process validation guidance document last November, I applauded the revision. "Old-style process validation has finally died," I said in my December editorial. After reviewing some of the 45 comments that members of industry have submitted on the draft, however, I now see that one important gap relates precisely to old validation—for products now in commercial production.

Laura Bush

In particular, several companies asked whether legacy products will require revalidation or increased process verification during routine production. "It may be burdensome and unwarranted to apply some of the new expectations to legacy products with a successful history of commercial production," Baxter noted in its submitted comments.

AstraZeneca also raised concern. "The [new] thinking is different and relies heavily on data generated early in the lifecycle of the product which may not always be available for older products," the company's comment says. "This is particularly important in light of the fact that retrospective validation is not recognised in the new guideline; it only references prospective and rarely permits concurrent [validation]."

Indeed, industry should not be expected to revalidate processes for existing products.

Other comments submitted raise additional concerns that the agency should consider. An important one relates to the burden of ongoing process monitoring. In particular, several companies said that the document's recommendation that sampling during commercial production be conducted at the same level as during validation would be an unnecessary burden. "As more confidence is obtained in the robustness and capability of the process, reduced testing should be allowed, if justified by the ever increasing process knowledge obtained for the product," the Pfizer comments say.

Wyeth voiced similar concerns, saying that the recommendation to continue the same sampling and testing regimen after process qualification is inconsistent with the application of quality risk management and scientific methods. "While heightened sampling and testing may be appropriate, based on a risk assessment, it may not be necessary to conduct the same level as established during qualification," the company said.

In spite of these concerns, the companies and organizations that submitted comments said they welcomed the revised guidance and its reflection of the concepts outlined in the International Conference on Harmonization (ICH) Q8, Q9, and Q10 documents. Several noted that the terminology, however, needs to be better aligned with that used in ICH Q8–Q10, and backed up by a glossary to avoid confusion.

A much broader concern about consistency, however, was voiced by the Biotechnology Industry Organization (BIO). "We ask FDA to ensure alignment within the inspectorate and review groups and between the review and inspectorate groups." Too many companies can cite examples of being chastised by one branch of the agency for following recommendations issued by another. It may not be possible to capture intra-agency alignment in the guidance document itself, but ensuring consistency in practice may be the most critical factor in determining the success of the new guidance.

If the agency can achieve that, and also make revisions to address key industry concerns, it will truly usher in a new era of process validation.

Laura Bush is the editor in chief of BioPharm International, lbush@advanstar.com